Frequency and Clinical Features of Space Headache Experienced by Astronauts During Long-Haul Space Flights

Background and Objectives Few anecdotal cases and 1 small retrospective study during short-duration space missions suggest that headache may occur early in flight, as part of the space motion syndrome. Whether headaches may also occur at later stages of space flights is unknown. We aimed to prospectively characterize the incidence, timing, clinical features, and management of space headaches during long-duration flights. Methods We prospectively evaluated the occurrence, characteristics, and evolution of space headaches and the effects of treatment and countermeasures during long-haul flights with onboard questionnaires and correlated them with prevailing temperature, pressure, and ambient O2 and CO2 levels, measured within the International Space Station. In addition, we analyzed retrospective headache data from a different astronaut cohort. Headache data were reported using descriptive statistics and correlation data with intraindividual logistic regression models. Astronauts were included through (inter)national aerospace organizations. Results In the prospective study, 22/24 (91.7%) astronauts (mean ± SD age: 46.6 ± 6.5 years, 95.8% male) experienced ≥1 episode of headache during a total of 3,596 space days. A total of 378 episodes were reported (median 9; range 1–128) with detailed information on 189. Phenotypically, 170/189 (89.9%) episodes were tension-type headache (TTH) and 19/189 (10.1%) were migraine. Episodes in the first week differed from those in later periods in terms of phenotype (migraine 12/51 [23.5%] vs 7/138 [5.1%]; TTH 39/51 [86.5%] vs 131/138 [94.9%]; overall p = 0.0002) and accompanying symptoms: nausea: 17.6% vs 6.9%, p = 0.05; vomiting: 9.8% vs 0.7%, p = 0.005; nasal congestion: 52.9% vs 29.7%, p = 0.004; facial edema: 41.2% vs 1.4%, p < 0.001; and duration (p = 0.001). Severity and treatments were similar: acute antiheadache medication: 55.6%; other medication: 22.4%; and alternative treatments: 41.1%. Headache occurrence was not associated with temperature or ambient pressure/levels of O2 and CO2 (all p > 0.05). In the retrospective study, 23/42 (54.8%) astronauts (43.5 ± 7.2 years, 90.5% male) reported experiencing ≥1 headache episode during mission. Nasal congestion was the most common (8/33; 24.2%) accompanying symptom. Seventeen of 42 astronauts have been previously described. Discussion Astronauts during space flights frequently experience headaches. These most often have characteristics of TTHs but sometimes have migrainous features, particularly during the first week of flight in astronauts without a history of recurrent headaches before or after the space flight.


Introduction
Space flight-induced microgravity affects the function of multiple body systems, including the brain. 1,2In retrospective studies, approximately 70% of astronauts who did not experience recurrent headaches on the Earth reported headaches, including migraines, during short-term space missions. 3,4pace headache has now been included in the International Classification of Headache Disorders, third edition (ICHD-3) classification as a secondary headache. 5It mainly occurs during the first few days of a space flight and is possibly related to space motion sickness. 6,7Anecdotal reports suggest that space headache may also occur at later stages of prolonged space flight, possibly because of prolonged microgravity. 1ata on whether headaches do occur at later stages of space flights are lacking.
We wanted to (1) better study whether the symptomatology and occurrence of space headache changed over the course of a space flight, (2) study whether this might be due to prolonged microgravity or other possible mechanisms, and ( 3) study what therapy is effective in treating space headache.To this extent, we investigated a cohort of astronauts during the early and late phases of long-term space flights aboard a space station.Data were retrospectively collected initially and then prospectively confirmed in a different group.Studying space headaches in otherwise "super healthy" people without a history of recurrent headaches on the Earth might enhance the understanding of headache in general and migraine particularly.

Methods
The prospective and retrospective data of the study were collected and analyzed separately.To this extent, we investigated a uniquely large cohort of 66 astronauts during the early and late phases of long-term space flights aboard a space station.We prospectively collected data from 24 astronauts and confirmed it with retrospective data from 42 astronauts.
Headache Questionnaires (Both Studies) Questionnaires that were developed were based on the criteria of the International Classification of Headache Disorders, 2nd (ICHD-2) 8 and 3rd (ICHD-3) editions. 5In accordance to the ICHD-2 and ICHD-3, the term "stress" was not specified in the question "whether headache was aggravated by stress."

Participants
All astronauts from the European Space Agency (ESA), National Aeronautics and Space Administration (NASA), and Japan Aerospace Exploration Agency (JAXA) that were assigned to International Space Station (ISS) expeditions from November 2011 to June 2018 were eligible to participate.We aimed at including long-term data from 24 astronauts.

Design
In each astronaut, baseline preflight data were collected 2-6 months before the launch.Astronauts had to complete a questionnaire about their individual headache history before the flight.The preflight questionnaires were coded and anonymized before analysis.Data during the flight were collected using 2 specific types of questionnaires: a daily questionnaire for the first 7 days of the space flight and a weekly questionnaire to be completed each following week throughout the stay in the ISS.The questionnaires were provided digitally through the data system on board the Soyuz vehicle and the ISS, daily for the first week and then weekly until the end of the mission.When more than 1 headache episode occurred per day (in week 1) or per week (after week 1), crew members were required to describe the most severe episode in the questionnaire.ESA, NASA, and JAXA employees and contractors provided and deployed the data software system on the ISS and scheduled all briefings, data collection intervals, and debriefings about the calendars and timelines of the crew members.A semistructured telephone debriefing interview was conducted within 3 months of the flight's return to clarify any unclearly reported details (A.A.V.; W.P.J.v.O.).

Data Transfer and Storage
In-flight data were downlinked in encrypted form and provided in encrypted and password-protected files by ESA User Operations Center.Both hard copy preflight and digital inflight data were sent from the NASA/ESA to the investigators through the Danish Aerospace Company.Data were then stored in the password-protected server of the Department of Neurology of Leiden University Medical Center (LUMC), where only the study team had access to.LUMC's systems are designed for sensitive data and follow all data guidelines.retrospective study provided written informed consent.Completed questionnaires were returned to the study team through the NASA/ESA.All questionnaires received were used for analysis.One astronaut participated in both the prospective and retrospective studies.

Outcomes
The primary outcome was the occurrence of headache episodes and accompanying symptoms.Headache episodes were defined as periods of headache, preceded and followed by headache-free intervals of at least 4 hours, and classified according to the ICHD-3 criteria. 5Headache severity was subjectively rated using an 11-point numeric rating scale (0 = no headache; 10 = worst headache imaginable [nondefined]).Preflight headaches were rated as mild, moderate, or severe.Other headache characteristics, associated symptoms, and use of medication were scored in a dichotomous manner.Used medications were specified.For assessing the short-term effects vs long-term effects of microgravity in the prospective study, we compared the headache episodes from week 1 with later headache episodes.These later episodes were further categorized as within or after the first 13 weeks of mission (halfway mission duration).
In addition to the clinical data, the following ambient data within the ISS were collected on a minute-to-minute basis during the prospective study: levels of carbon dioxide (% relative to total pressure) and oxygen (% relative to total pressure), partial pressure (carbon dioxide; oxygen; millibar), temperature (degrees Centigrade), and relative humidity (percentage).Data were collected using standard NASA/ESA methods and transferred to the study team through the Danish Aerospace Company.

Statistical Analysis
Analysis of headache data in both studies was performed using a descriptive clinical approach, using chi square tests, McNemar tests, or Fisher exact tests, where appropriate.In the prospective data analysis, data from the 1 participant in short-haul flight were not included because the duration of the space flight was only 10 days.An intraindividual prediction logistic regression analysis was used to determine the relationship between the occurrence of headache during the week and average CO 2 level (M.J.L.P.).Mission time was used as a within-subject repeated factor and age at launch as covariate.For the analysis of ambient data in relation to occurrence of headaches, we used headache and ambient data from week 3 until the end of a mission.Ambient data were preprocessed: because the diary entries were based on the previous week, average CO 2 (and O 2 , humidity, temperature, and pressure) levels were calculated over the 7 days before diary entry dates.For some weeks, these measurements were not available and were therefore set as missing in the analyses.Analyses were performed in SPSS 23.0.0 (SPSS Inc., IBM, Armonk, NY), except for the ambient data analysis using MATLAB R2013a (Mathworks, Inc., Natick, MA).

Standard Protocol Approvals, Registrations, and Patient Consents
The study protocol (Pro 0695) was approved by the ESA Medical Board, NASA Johnson Space Center Committee for the Protection of Human Subjects, later by Johnson Space Center Institutional Review Board, JAXA Institutional Review Board for Human Research, and after that by the ISS Human Research Multilateral Review Board.All astronauts were briefed on the study protocol at the Informed Consent Briefings (A.A.V.) and provided written informed consent before participation in the study.
Both studies were additionally approved by the medical ethics committee of LUMC.All astronauts provided written informed consent before participation.The funders of the studies reported here had no role in study design, data collection, data analysis, data interpretation, or writing of the report.All authors had full access to all the data in this study, and the corresponding author had final responsibility for the decision to submit for publication.

Data Availability
Data not provided in the article because of space limitations may be shared at the request of qualified investigators for the purpose of replicating procedures and results.

Participants
Of the 39 eligible ESA, NASA, or JAXA crew members who visited the ISS from November 2011 until June 2018, 31 (86.1%)consented before the flight to participate during a total of 21 ISS expeditions (missions 30-56).In 5/31 (19.4%) astronauts from whom baseline data were obtained, in-flight participation was cancelled due to time constraints.Two astronauts did not participate in the in-flight study because the preset number of participants was reached, leaving 24 in-flight participants (Figure 1).All participants completed the study.The study period consisted of 3,596 days of in-flight data collection.In-flight data were missing from 9 measurement points (3 daily questionnaires; 6 weekly questionnaires) due to technical issues, omitting 45/3,596 days (1.3%) from 8 crew members from 7 ISS expeditions from the final analysis.There were no missing data from baseline Earth-based time points.

Headache Episodes
The preflight headache history is summarized in Table 1: 9/24 (37.5%) astronauts reported never having any headaches, and 3/24 (12.5%) had had a headache interfering with daily activities in the past 12 months.None of them had a history of recurrent headaches or had ever been diagnosed with migraine.
As specified in the Methods section, for assessing the shortterm effects vs long-term effects of microgravity, we compared the occurrence and symptomatology of headache episodes in the first week of the space flight with those at later stages.The later headache episodes were further divided into those occurring in the first half of the space mission (excluding the first week) and those occurring in the second half.
The occurrence and characteristics of the headaches during space flight and the accompanying symptoms are summarized in Table 2.In total, 378 headache episodes were reported in-flight by 22/24 (91.7%) astronauts (vs 9/24 [37.5%] preflight; p = 0.0005).The median individual headache frequency was 9 (range 1-128), with >50 episodes reported by 2/22 (9.0%) astronauts and <10 episodes reported by 11/22 (50.0%).Of the 22 astronauts who reported ≥1 headache episode, 2 (9.0%) reported headaches only in the first week and 9/22 (40.9%)only in the first 13 weeks of the mission (first week included).Headaches never occurred only in the second half (weeks 14-26) of the mission.Thus, if astronauts had headaches in the second half of the flight, they also had had headaches in the first half.In 8/22 (36.4%) astronauts, headaches only occurred from week 2 onward (7/8 had ≥50% of headaches in weeks 2-13 and 4/8 had ≤4 headache episodes).Occurrence of headache episodes is graphically depicted in Figure 2, A and B.

Headache and Environmental Factors in the ISS
Weekly mean CO 2 levels, O 2 levels, humidity, temperature, or pressure did not differ from weeks in which an individual astronaut experienced headache vs weeks wherein the astronaut did not experience a headache (eTable 2, links.lww.com/WNL/D465).In addition, there was no correlation between mean CO 2 levels,O 2 levels, and individually reported headache episodes (Figure 4).

Retrospective Study
Participants In 2016, retrospective questionnaires were sent out through the agencies in 1 batch (with 1 reminder) to all astronauts who had flown between 2006 and 2016, except for the 17 astronauts who had already been published before. 4Of the 67 eligible astronauts who were invited through the space agencies, 42 (63%) agreed to participate and returned the questionnaire by July 2019.Of these, 38/42 (90.5%) were male.The mean age was 43.5 ± 7.2 years, and the mean mission duration was 134.6 ± 83.8 days (Table 3).Data from 17 astronauts have been previously reported. 4adache Occurrence and Characteristics A total of 23/42 (54.8%) astronauts reported 33 headache episodes at any time during in-orbit space flight.Headaches were mostly of mild-to-moderate severity (31/33; 93.9%) and monotonous or heavy in quality (32/33; 97.0%) with transient vertigo, nausea, and photophobia during the first week.Nasal congestion (6/33; 12.8%) was the most commonly reported associated symptom (eTable 1, links.lww.com/WNL/D465).Of all 33 episodes, 2 (6.1%) were classified as migraine or probable migraine, both occurring in the first week of mission.

Discussion
We investigated the occurrence, timing, and characteristics of headache and possible associated symptoms during long-term space-flights in 66 super healthy astronauts, who did not have regular headaches previously in the Earth.Prospective data were collected in 24 astronauts, and retrospective data from 42 astronauts were used to confirm the prospective findings.We found that episodes of headache were provoked throughout the space flight, but with different symptomatology and incidence.Whereas a migraine phenotype with associated nausea, vomiting, facial edema, and nasal congestion was more prevalent in the first week, a TTH phenotype predominated in the later phases of microgravity.Occurrence of headache episodes declined and duration of headache episodes shortened with longer stay in microgravity.There was no correlation of space headache with changes in ambient parameters in the space missile or station.After returning to the Earth, none of the astronauts reported any headaches again.
We can only speculate about the etiology of space headache.Two different mechanisms might play a role.In the first week, adaptation to weightlessness occurs with a prominent role for the vestibular system.This phenomenon is described by the vestibular sensory conflict hypothesis. 7Loss of tilt-related otolith signals in the absence of normal gravity is suggested to cause a conflict between actual and anticipated signals from sensory organs subserving spatial orientation.Sensory conflict is considered the primary cause of space motion sickness of which headache is the most frequently reported symptom. 7,9,10esults from our study support this assumption: we found that headache in combination with transient nausea, vomiting, and vertigo almost exclusively occurred during the first week in flight.
During longer stay in space, the cephalad redistribution of body fluids might result in intracranial and extracranial fluid shifts, increasing the intracranial pressure and triggering headaches (eFigure 1, links.lww.com/WNL/D465).This hypothesis is appealing because cephalad fluid shifts of >100 cc are not very likely to be without functional consequences. 11,12e showed that the clinical picture of space headache after the first week in microgravity resembles the milder forms of on-Earth headache due to intracranial hypertension, in which a phenotypically TTH is the main and most common symptom. 13Simultaneously, we have observed remarkable interindividual differences in headache patterns, suggesting not-yet identified susceptibility factors must play an additional role.
Of interest, the most commonly reported associated symptom was nasal congestion, which is caused by swelling of the nasal mucosa due to this increase in extracerebral fluid volume.Papilledema and progressive visual loss are linked to on-Earth intracranial hypertension. 14,15A recent study reported additional evidence for this hypothesis: visual symptoms and/or ocular abnormalities (optic disc swelling, globe flattening, choroidal folds, and hyperopic shifts in refraction) occur in 29%-60% of astronauts post flight.These are interpreted as signs of the visual impairment intracranial pressure (VIIP) syndrome, postulated to be the result of increased intraocular pressure due to microgravity. 16In addition, MR studies of the brains of astronauts showed a reversible increase in ventricular volumes post flight, 1,17 and there is evidence for persisting CSF circulation disturbances many months after return to the Earth. 18This might explain in-flight space headache and ocular/visual abnormalities after long-duration spaceflight.
In-flight gravitational countermeasures such as exercise and transient enhanced artificial gravity aim to limit the effect of microgravity-induced physiologic changes. 12Previously, we reported that headache intensity and accompanying symptoms decreased with countermeasures in an on-Earth simulation model. 19High-intensity exercise is suggested to decrease intracranial pressure 12 and could thereby also limit the burden of microgravity-induced headaches.Although our study was not primarily aimed at assessing the effects of countermeasures, astronauts did often report headache relief after sleep, exercise, rehydration, and coffee intake.Intake of analgesics, mainly NSAIDs, was also reported as an effective relief in many headache episodes.Previously, increased onboard CO 2 levels had been related to the occurrence of headache episodes. 20We could not confirm this in our prospective study.Few studies investigated the effect of microgravity on pain.Most addressed back, leg, or abdominal pain 21,22 with little detail for headache characteristics. 21Although headache has been sporadically reported as a common symptom in space, detailed analysis of the clinical characteristics was lacking. 3,23,24arlier publications from our group, using data from retrospective and simulation studies, are well in line with the results from this study. 4,19,25Space headache has now been recognized as a new entity in the ICHD. 5 Our study has several strengths.We were able to comprehensively and prospectively monitor headache and associated symptoms during an actual long-term stay in space in 66 astronauts.Because of logistic and financial reasons, such data are usually collected during on-Earth studies with simulated microgravity 19,21 or directly after return from Space. 22Only sleep quality in space has been studied in a similar prospective manner. 2 With our prospective findings, we confirmed previous retrospective in-flight 4 and simulated microgravity data. 19,25A total of 66 astronauts is substantial in space medicine research. 26Unfortunately, because there were only 5 female astronauts in our study, we cannot reliably extend our findings to women, in whom headache is more common on the Earth. 27Missing data were very few, and the findings in the retrospective and prospective parts of the study were consistent and complimentary, increasing the validity of our observations. 26 conclusion, space flights provoked headaches in super healthy people who did not have regular headaches before and after the space mission. 28,29space headaches occurred during the whole mission, but most often in the first week and were then often of the migraine type.Space headaches occurring in later stages of the flights were less frequent and mainly of a TTH, suggesting a different underlying mechanism.Further research is needed to unravel the underlying mechanisms of space headache and translate them to headaches occurring on the Earth.In addition, more effective therapies need to be developed to combat space headaches because for many astronauts, this a major recurring disabling problem during space flights.
Design, Participation, and Data Collection Between 2006 and 2016, paper headache questionnaires were sent to all ESA and NASA astronauts who had flown on space missions.All astronauts who agreed to participate in the Glossary CSA = Canadian Space Agency; ESA = European Space Agency; ICHD-2 = International Classification of Headache Disorders, second edition; ICHD-3 = International Classification of Headache Disorders, third edition; IQR = interquartile range; ISS = International Space Station; JAXA = Japan Aerospace Exploration Agency; LUMC = Leiden University Medical Center; NASA = National Aeronautics and Space Administration; TTH = tension-type headache.

Figure 1
Figure 1 Flowchart of Astronaut Inclusion and Exclusion in the Prospective Study

Figure 2
Figure 2 Occurrence of Headache Episodes During Space Flight in Individual Astronauts

Figure 3
Figure 3 Occurrence of Headache Episodes During Long-Term Space Travel in 24 Astronauts Declines After the First Week in Space

Figure 4
Figure 4 Graph Showing There Was No Relation Between Partial CO 2 and Partial O 2 Levels and Weekly Headache Incidence in Individual Healthy Astronauts During Long-Term Stay at the ISS

Table 2
Characteristics of Space Headache Episodes During First and Later Weeks of Space Travel in the Prospective Study

Table 3
Baseline Characteristics and Headache Occurrence Among Astronauts During Space Flight, Based on a Retrospective Questionnaire Study Abbreviation: EVA = extra vehicular activity; NSAID = nonsteroidal anti-inflammatory drug.a Before or after flight headache on the Earth (2016)/before flight headache on the Earth (2008).